Targeted Transcriptomic Analysis of C57BL/6 and BALB/c Mice During Progressive Chronic Toxoplasma gondii Infection Reveals Changes in Host and Parasite Gene Expression Relating to Neuropathology and Resolution

Abstract

Toxoplasma gondii is a resilient parasite that infects a multitude of warm-blooded hosts and results in a lifelong chronic infection requiring continuous responses by the host. Chronic infection is characterized by a balanced immune response and neuropathology that are driven by changes in gene expression. Previous research pertaining to these processes has been conducted in various mouse models, and much knowledge of infection-induced gene expression changes has been acquired through the use of high throughput sequencing techniques in different mouse strains and post-mortem human studies. However, lack of infection time course data poses a prominent missing link in the understanding of chronic infection, and there is still much that is unknown regarding changes in genes specifically relating to neuropathology and resulting repair mechanisms as infection progresses throughout the different stages of chronicity. In this paper, we present a targeted approach to gene expression analysis during T. gondii infection through the use of NanoString nCounter gene expression assays. Wild type C57BL/6 and BALB/c background mice were infected, and transcriptional changes in the brain were evaluated at 14, 28, and 56 days post infection. Results demonstrate a dramatic shift in both previously demonstrated and novel gene expression relating to neuropathology and resolution in C57BL/6 mice. In addition, comparison between BALB/c and C57BL/6 mice demonstrate initial differences in gene expression that evolve over the course of infection and indicate decreased neuropathology and enhanced repair in BALB/c mice. In conclusion, these studies provide a targeted approach to gene expression analysis in the brain during infection and provide elaboration on previously identified transcriptional changes and also offer insights into further understanding the complexities of chronic T. gondii infection.

Oestradiol Contributes to Differential Antitumour Effects of Adjuvant Zoledronic Acid Observed Between Pre- and Post-Menopausal Women

“…Oestradiol did not affect the numbers of tumours that developed in bones or soft tissues of immunocompromised BALB/c nude mice and only partially affected the number of tumour cells that developed in the soft tissues of BALB/c mice. As BALB/c nude mice have no T cells and reduced innate immunity and immunocompetent BALB/c mice elicit less of an immune response when faced with challenge compared with C57BL/6 mice ( 39 ), our data suggest that oestrogen effects on antitumour immune response may play important roles in how this hormone regulates tumour cell dissemination and metastatic outgrowth. In agreement with a potential role for the immune response in regulating soft tissue metastases, reducing oestradiol concentrations to those observed in postmenopausal women resulted in significant increases in tumour volume in the soft tissues of immunocompetent BALB/c and C57BL/6 mice but did not affect growth of tumours in the soft tissues of immunocompromised mice ( Figure 3 ).…”

Neutrophils in the brain are sources of neuroprotective molecules and demonstrate functional heterogeneity during chronicToxoplasma gondiiinfection

“…However, underlying changes in neurochemistry and significant changes in the health of neurons [6,7] suggest a constant need to balance inflammation and protect against neuropathology. Recent work in our lab to determine Toxoplasma-induced changes in immunological and neurological transcripts in the brain [8] supports these neurological changes but also reveals potential neuroprotective pathways that remain poorly understood. The concept of neuroprotection and resolution of inflammation has been investigated in models of central nervous system (CNS) injury such as ischemic stroke and spinal cord injury and during experimental cerebral malaria (ECM) infection.…”

“…However, underlying changes in neurochemistry and significant changes in the health of neurons [6, 7] suggest a constant need to balance inflammation and protect against neuropathology. Recent work in our lab to determine Toxoplasma-induced changes in immunological and neurological transcripts in the brain [8] supports these neurological changes but also reveals potential neuroprotective pathways that remain poorly understood.…”

Review on diagnosis and molecular characterization of Toxoplasma gondii in humans and animals

“…With cat bioassays, even low bradyzoites containing tissue samples, if fed, can lead to oocyst shedding in feces (Dubey, 2006). In the murine model bioassay; GKO mice (Opsteegh et al, 2016), C57BL/6 mice (Tyebji et al, 2020;Bergersen et al, 2021), WT-BALB/c mice (Bergersen et al, 2021), SCID mice and Swiss Webster mice (Watson & Davis, 2019) are used in various laboratories. To overcome the disadvantages of bioassays (expensive, time consuming, requires live parasite and a large number of mice), reserachers also developed serological and molecular methods to detect parasitic antigen or antibody and DNA directly from the samples (Opsteegh et al, 2020).…”